Iron deficiency is common, and intravenous iron supplementation

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1 Can the Response to Iron Therapy Be Predicted in Anemic Nondialysis Patients with Chronic Kidney Disease? Simona Stancu,* Liliana Bârsan, Ana Stanciu, and Gabriel Mircescu* *Department of Nephrology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; and Dr. Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania Background and objectives: Anemia is iron responsive in 30 to 50% of nondialysis patients with chronic kidney disease (CKD), but the utility of bone marrow iron stores and peripheral iron indices to predict the erythropoietic response is not settled. We investigated the accuracy of peripheral and central iron indices to predict the response to intravenous iron in nondialysis patients with CKD and anemia. Design, setting, participants, & measurements: A diagnostic study was conducted on 100 nondialysis patients who had CKD and anemia and were erythropoiesis-stimulating agent and iron naive. Bone marrow iron stores were evaluated by aspiration. Hemoglobin, transferrin saturation index (TSAT), and ferritin were measured at baseline and 1 month after 1000 mg of intravenous iron sucrose. Posttest predictive values for the erythropoietic response (>1-g/dl increase in hemoglobin) of peripheral and central iron indices were calculated. Results: The erythropoietic response was noted in a higher proportion in bone marrow iron-deplete than in iron-replete patients (63 versus 30%). Peripheral iron indices had a moderate accuracy in predicting response. The positive (PPV) and negative predictive values (NPV) were 76 and 72% for a TSAT of 15% and 74 and 70% for a ferritin of 75 ng/ml, respectively. In the final logistic regression model, including TSAT and ferritin, the chances of a positive response increased by 7% for each 1% decrease in TSAT. Conclusions: Because an erythropoietic response is seen in half of patients and even one third of those with iron-replete stores responded whereas peripheral indices had only a moderate utility in predicting response, the therapeutic trial to intravenous iron seems to be a useful tool in the management of anemia in nondialysis patients with CKD. Clin J Am Soc Nephrol 5: , doi: /CJN Iron deficiency is common, and intravenous iron supplementation is a recognized therapy of anemia in long-term hemodialysis patients (HD), especially in those who are treated with epoetin (1 6). Several studies suggested that iron deficiency evaluated by bone marrow iron examination is common also in predialysis patients with chronic kidney diseases (CKD). In the reported series, the prevalence of bone marrow iron depletion varied widely from 23 to 90% (7,8). The role of iron supplementation in nondialysis patients with CKD is much less clear than in HD patients, although studies have reported a positive response to intravenous iron even without concomitant epoetin administration in 38 to 68% of patients (9 12). The prediction of erythropoietic response is clinically important, because the conventional markers of iron status serum ferritin level and transferrin saturation index (TSAT) although simple and relatively inexpensive, are not highly accurate in predicting response to iron in this population (5,7,8,11), and the safety of intravenous iron is a matter of concern in patients with CKD (13,14). Moreover, there are no published Received June 30, Accepted November 12, Published online ahead of print. Publication date available at Correspondence: Dr. Gabriel Mircescu, Calea Grivitei 4, Bucharest, Romania. Phone/Fax: ; gmircescu@hotmail.com data relating iron stores, peripheral iron indices, and the response to intravenous iron. We conducted a study to investigate the accuracy of peripheral and central iron status indices to predict the response to intravenous iron in nondialysis patients who had CKD and anemia and were erythropoiesis-stimulating agent and iron naive. Materials and Methods Study Design This was a single-center diagnostic study with a duration of 3 months. In a 2-month run-in period, renal function, anemia, and the other admission criteria were assessed. At baseline, a bone marrow aspiration was performed, peripheral iron indices were evaluated, and 1000 mg of iron sucrose was administered intravenously in 5 days, irrespective of iron status. One month after the last intravenous iron dose, blood was drawn for hemoglobin (Hb) and peripheral iron index evaluation. The reference test was the erythropoietic response, defined as a 1-g/dl increase in Hb level. Index tests were central (bone marrow iron stores, vide infra) and peripheral iron indices (TSAT and serum ferritin). The study was approved by the Helsinki committee of the hospital. Selection Criteria Anemia, defined as a Hb 11.0 g/dl (three measurements in the previous 8 weeks with 2.5-g/dl difference between highest and lowest values) and stages 3 through 5 CKD and mean estimated GFR Copyright 2010 by the American Society of Nephrology ISSN: /

2 410 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: , 2010 (egfr; abbreviated Modification of Diet in Renal Disease [MDRD] formula) (15) 60 ml/min per 1.73 m 2 (three measurements in the previous 8 weeks each separated by at least 1 week) were the inclusion criteria. Patients with any previous iron or erythropoiesis-stimulating agent therapy, active infectious conditions, cancer, iron overload (ferritin 800 ng/ml), blood transfusions and/or active bleeding within the preceding 3 months, hemolytic anemia, folate or vitamin B 12 deficiency, severe malnutrition (Subjective Global Assessment score of C on a scale of A through C) (16), or hypothyroidism were excluded. Similarly, patients with congestive heart failure (New York Heart Association class III or IV), severe uncontrolled high BP (systolic BP 190 mmhg and/or diastolic BP 115 mmhg), active liver disease (more than three times increase in alanine or aspartate amino transferase), uremic complications (pericarditis, polyneuropathy), severe hyperparathyroidism (intact parathyroid hormone 800 pg/ml), severe psychiatric disorders, or known hypersensitivity to any component of iron sucrose as well as those who were participating in other clinical trials or refused to sign an informed consent were not enrolled. Patients One hundred adults (age 18 yr) were selected from the patients who were admitted to a nephrology department during a 2-year period (Figure 1). Laboratory Tests Bone Marrow Parameters of Iron Status. Bone marrow was collected by aspiration from the sternum. The smears were prepared from marrow fragments, colored with Perls Prussian blue stain, and interpreted by a senior hematologist who had no knowledge of the patients iron status. Positive and negative controls were used for calibration. Additional slides from aspirate were prepared when necessary, and at least nine bone marrow particles were reviewed for a final diagnosis (17). The occurrence of siderotic granules in macrophages was Figure 1. Patient selection. graded on a scale from 0 to 6 (18). Patients with a score of 0 or 1 were considered iron deficient, those graded from 2 to 4 as having normal macrophage iron, and those graded from 5 to 6 as having macrophage iron overload. Erythroblasts with green-blue particles on Perls stain were defined as sideroblasts. According to the number of siderotic granules, sideroblasts were classified as type 0 (no granules), type 1 (one to three granules), or type 2 (three or more granules), and their percentages were computed (19). The pattern of bone marrow iron distribution was classified as normal (macrophage iron 2 to 4, sideroblasts in normal percentage), iron deficiency (macrophage iron 0 or 1, sideroblasts absent or in a very low percentage), iron overload (macrophage iron 5, sideroblasts in normal or increased percentage), and anemia of chronic inflammation (macrophage iron 5, sideroblasts absent or in very low percentage). The patients were classified according to bone marrow iron as deplete (bone marrow iron deficiency) or replete (normal iron stores, iron overload, or anemia of chronic inflammation). Peripheral Parameters of Iron Status. Serum ferritin and serum transferrin were measured by immunoturbidometric methods (Good Biotech, Taichung, Taiwan; Giesse Diagnostics, Rome, Italy) on an autoanalyzer Olympus AU400. Total serum iron-binding capacity was calculated as serum transferrin Serum iron was assessed by a colorimetric method (Giesse Diagnostics). TSAT was calculated as the percentage of serum iron from total serum iron-binding capacity. Other Parameters. C-reactive protein (CRP) was assessed by a high-sensitivity latex immunoturbidometric method (Giesse Diagnostics). Statistical Analysis Data are presented as mean SD, 95% confidence interval (95% CI), or median and interquartile range, according to their distribution. A t test, paired or not, Mann-Whitney, 2, or Wilcoxon test was used to compare groups, as required. Receiver operating characteristic (ROC) curves (20 22) were created using the erythropoietic response as reference test (dichotomous variable) and macrophage iron score, ferritin, and TSAT and their combination as continuous variables. The effect of combining tests (TSAT and ferritin) was tested according to Trieppi et al. (23). The diagnostic accuracy was evaluated by sensitivity and specificity. Posttest positive probability of response in case of a positive test and of a nonresponse in case of a negative test was calculated at various cutoff values (24,25). Because the reported prevalence of nondialysis patients who had CKD and responded to intravenous iron therapy varied between 38 and 68% (9 12), a prevalence of 40% was used to calculate the posttest probability of response. The relationship between the erythropoietic response (present versus absent) and relevant parameters was investigated by multivariable binominal logistic regression. Considering a probability of 50% for a 1-g/dl increase in Hb and a presumed clinically significant difference among groups of 10%, at least 27 patients per group would be required for a 95% probability and a power of 95%. Statistical analyses were performed with Analyze-it (Analyze-it Software, Ltd., Leeds, UK) and SPSS (SPSS Inc., Chicago, IL) packages.

3 Clin J Am Soc Nephrol 5: , 2010 Can Response to Iron Be Predicted? 411 Results One hundred patients were enrolled and accomplished the study. Median age was 62 years (range 24 to 84); 55% were older than 60 years. There was a slight male preponderance (55%). Vascular nephropathies and primary glomerulonephritis were main causes of CKD, whereas diabetic nephropathy was rare (43, 36, and 3%, respectively). Median egfr was 14 ml/ min per 1.73 m 2 (interquartile range 10 24); most patients were in stage 4 or 5 CKD (28 and 56%). Inflammation was highly prevalent, but nutritional status was good, because 60% of patients had a serum CRP 10 mg/l, whereas 65% had a Subjective Global Assessment score of A and 75% a serum albumin 4 g/dl (Table 1). Anemia was severe: the mean Hb was 8.99 g/dl, and in 70% of cases, the initial Hb was 10 g/dl. Bone marrow iron stores were depleted in 48% of patients. Using conventional cutoffs for peripheral iron indices (TSAT 20% and ferritin 100 ng/ ml), the proportions of patients below cutoff were 33, 31, and 17% for the combination of tests (TSAT 20% and ferritin 100 ng/ml), respectively. One month after 1000 mg of intravenous iron, the mean Hb attained was 10.0 g/dl, with a g/dl mean increase. Hb increased by 1 g/dl in 48% of patients. In univariable analysis, the responders were younger and a higher proportion were in stage 4 CKD, but otherwise their general characteristics were similar to those of the nonresponders (Table 1). A macrophage iron score of 1, reflecting deplete iron stores, was more frequent in responders than in nonresponders (63 versus 33%), whereas the opposite was true in the case of patients with bone marrow iron overload (a macrophage iron score 3): 6 versus 29%. The proportion of responders was twice as high in patients with iron-deplete versus iron-replete stores (63 versus 30%). Similarly, the peripheral iron indices were different. Median TSAT and ferritin were lower in responders. Using cutoff values of 20% for TSAT and 100 ng/ml for ferritin, the percentages of patients with lower than cutoff values were significantly higher in responders than in nonresponders: 50 versus 17%, 48 versus 15%, and 33 versus 2% for the combination of tests, respectively (Figure 2). The sensitivity and the specificity of central and peripheral iron indices to identify the erythropoietic response was similar and moderate. Areas under the ROCs were approximately 70% and did not differ from one test to another. The combination of TSAT and ferritin was not superior to each test in predicting response (Figure 3). When examining the accuracy of the central and peripheral iron indices to identify a positive erythropoietic response at different cutoff values, the sensitivity was low, whereas the specificity was high (i.e., nonresponders were better identified by a negative test; Table 2). The posttest PPV and NPV for response of peripheral iron indices were balanced at cutoffs of 15% for TSAT (mean 0.76 [95% Cl, 0.50 to 0.93] and 0.72 [95% Cl, 0.64 to 0.79]) and 75 ng/ml for ferritin (mean 0.74 [95% Cl, 0.46 to 0.92] and 0.70 [95% Cl, 0.62 to 0.77]). In the case of a low macrophage iron score, sensitivity and specificity were 60%, but the PPV was low (mean 0.55 [95% Cl, 0.40 to 0.69]), whereas the NPV was higher (mean 0.74 [95% Cl, 0.60 to 0.85]). The same was true when bone marrow iron stores (deplete versus replete) were examined. Inflammation had a low influence on both iron indices and response. Neither median CRP nor the proportion of patients with CRP 10 mg/l was different in responders as compared with nonresponders. No correlation was found between ferritin and CRP, and the proportions of responders were similar when evaluated at different CRP cutoffs (data not shown). In multivariable logistic regression analysis, the final model included only TSAT and ferritin and predicted 19% of the variability of the erythropoietic response (Table 3). Only TSAT made a significant contribution (i.e., the chances of response increased with 7% for each 1% decrease in TSAT). Discussion This is one of the largest studies to evaluate the accuracy of central and peripheral iron indices to predict the response to intravenous iron in nondialysis patients with CKD. It confirms that bone marrow iron stores are depleted in an important proportion of the nondialysis patients with CKD and anemia and brings further support to the therapeutic intravenous iron test, because the predictive values of iron indices are only moderate. Few data are available about the prevalence of iron deficiency in nondialysis patients with CKD, because the bone marrow examination the gold standard in iron deficiency diagnosis is seldom performed. On the basis of bone marrow examination, 48% of our patients had deplete iron stores, a lower percentage than reported by Silverberg and colleagues (9) (90%) but higher than in data reported by Rahman et al. (8) (23%). Part of this wide variation could be attributed to the method of examination. In the study by Silverberg and colleagues (9), the bone marrow iron evaluation was not detailed, Rahman et al. (8) used only the number of macrophage siderotic particles, and we used a more complex examination, involving not only macrophage iron but also sideroblasts; however, our data support a significant prevalence of deplete bone marrow iron stores in nondialysis patients with CKD in advanced stages, not very different from reports of HD patients who were on epoetin therapy (40 to 63%) (4,26). Bone marrow iron is almost never used for clinical decision in day-to-day practice, and decisions are instead based only on peripheral iron indices. Typical markers of iron deficiency and cutoff values used in HD patients are a TSAT 20% and a ferritin 100 ng/ml. Kidney Disease Outcomes Quality Initiative (KDOQI) recommend these levels also for nondialysis patients with CKD (1). The proportions of patients who were below these cutoffs in our study were 33, 31, and 17% for the combination of TSAT and ferritin, respectively. By comparison, in Third National Health and Nutrition Examination Survey (NHANES III) cohort, in nondialysis patients with CKD and anemia (GFR 30 ml), only 35% of women and 33% of men had both a TSAT 20% and a ferritin 100 ng/ml (27). The higher proportions in NHANES III cohort, despite a lower percentage of patients with stage 5 CKD, could indicate that these cutoffs are not

4 412 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: , 2010 Table 1. Characteristics of patients, according to the response to intravenous iron IV (n 100) Characteristic All (n 100) Responders (n 48) Nonresponders (n 52) P a Age (years) mean SD yr (%) Male gender (%) Primary renal disease (%) 0.9 glomerulonephritis interstitial nephropathies ADPKD vascular disease diabetic nephropathy egfr (ml/min; median IQR ) 14 (10 24) 17 (11 24) 13 (8 25) 0.8 CKD stage (%) Body mass index (kg/m 2 ) mean SD to 25.0 (%) Subjective global assessment score A (% patients) Serum albumin (g/dl) mean SD serum albumin 4 g/dl (%) CRP (mg/l) median (IQR) 15 (6 30) 15 (7 41) 15 (6 25) mg/l (%) Hb (g/dl) mean SD g/dl (%) TSAT (%) median (IQR) 23 (13 30) 18 (10 25) 26 (22 32) % Serum ferritin (ng/ml) median (IQR) 176 (79 300) 114 (51 197) 230 ( ) ng/ml (%) TSAT 20% and ferritin 100 ng/ml (% patients) Macrophage iron score (% patients) Bone marrow iron deplete (%) Erythropoietic response (g/dl) Hb (at assessment) Hb Response defined as 1-g/dl increase in Hb. ADPKD, autosomal dominant polycystic kidney disease; IQR, interquartile range. a Iron deplete versus iron replete. appropriate and may falsely identify too many patients as being iron deficient (27). Given these uncertainties, we initiated iron therapy in all patients, irrespective of their bone marrow iron status or peripheral iron indices. We chose to give iron intravenously, not orally, because studies (11,28) suggested a benefit of the intravenous route in patients with

5 Clin J Am Soc Nephrol 5: , 2010 Can Response to Iron Be Predicted? 413 Figure 2. Percentages of positive peripheral or bone marrow iron tests, according to the response to 1000 mg of intravenous iron ( 1-g/dl increase in Hb) in 100 nondialysis patients with CKD. sferr, serum ferritin. *P Figure 3. Sensitivity and specificity of TSAT and serum ferritin (ferritin) and their combination (TSAT ferritin) and bone marrow iron (BM iron) to identify correctly a positive erythropoietic response ( 1-g/dl increase in Hb [ Hb]) to intravenous iron in 100 nondialysis patients with CKD (areas under the ROCs). The areas under the ROCs do not differ in the case of TSAT, ferritin, and BM iron, but TSAT ferritin area under the ROC is significantly lower than the other. *P 0.05 versus TSAT and ferritin. characteristics similar to our cohort (initial low Hb and GFR and lack of epoetin therapy). In addition, a recent metaanalysis showed a small but significant difference in Hb level favoring the intravenous iron route (29). After intravenous iron sucrose administration, a significant hematologic response was noted in the whole cohort: 48% had a 1-g/dl increase in Hb, and 26% of patients attained 11 g/dl Hb. A 1-g/dl increase in Hb after intravenous iron is a useful predictive test for a positive response to iron therapy, recommended by KDOQI (1) in case of discordant iron indices, a position sustained by the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study results in HD patients (30). In nondialysis patients with CKD, the reported proportion of responders only to intravenous iron were 68% (9), 44% (10), 38% (11), and 39% (12). Thus, a 40% prevalence of responders in this population would be reasonable and could be safely used for the evaluation of posttest probability of response. Although at first look both peripheral and central iron indices could differentiate responders from nonresponders (Figure 2, Table 1), the areas under the ROCs were approximately 70%, reflecting a moderate clinical utility (Figure 3). Of note, even 30% of patients with adequate iron stores responded. Furthermore, when predictive values were examined at different cutoffs, only a TSAT 15% and a ferritin 75 ng/ml performed clinically better, predicting a positive response in 70% of cases and excluding a negative response in the case of a negative test with a probability of approximately 70%. These cutoff values are closer to limits of nondialysis patients with CKD than to those of HD patients, in accordance with Fishbane s (31) assumption. In logistic regression, the utility of peripheral and bone marrow iron indices was also moderate; because only TSAT and ferritin were retained in the final model, a 1% lower TSAT increased the response chances by 7%. This is in line with a recent analysis of NHANES data, in which the percentage of nondialysis patients with CKD and anemia had a decreasing trend in TSAT but not in serum ferritin quartiles (32). In other studies that investigated the relationship between iron indices and response in nondialysis patients with CKD, the prognostic value of TSAT and serum ferritin for the erythropoietic response was also of marginal clinical utility. In a study by Van Wyck et al. (11), these tests proved unhelpful, but patients had a higher egfr, the anemia was less severe, TSAT was lower, and ferritin was higher than in our cohort, which can partially explain the differences. Similarly, Silverberg and colleagues (9)

6 414 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: , 2010 Table 2. Sensitivity, specificity, and the predictive values of peripheral and bone marrow indices to predict the erythropoietic response to intravenous iron in nondialysis patients with CKD Parameter Sensitivity Specificity Posttest Predictive Value a For Response if Test Positive For Nonresponse if Test Negative TSAT (%) (0.18 to 0.45) 0.90 (0.79 to 0.97) 0.68 (0.36 to 0.90) 0.66 (0.59 to 0.73) (0.33 to 0.62) 0.90 (0.79 to 0.97) 0.76 (0.50 to 0.93) 0.72 (0.64 to 0.79) (0.48 to 0.77) 0.80 (0.67 to 0.90) 0.68 (0.49 to 0.84) 0.77 (0.66 to 0.85) (0.61 to 0.87) 0.51 (0.37 to 0.65) 0.51 (0.39 to 0.62) 0.76 (0.59 to 0.88) Ferritin (ng/ml) (0.12 to 0.37) 0.94 (0.84 to 0.99) 0.72 (0.33 to 0.95) 0.65 (0.59 to 0.70) (0.27 to 0.56) 0.90 (0.79 to 0.97) 0.74 (0.46 to 0.92) 0.70 (0.62 to 0.77) (0.34 to 0.64) 0.82 (0.69 to 0.92) 0.65 (0.43 to 0.83) 0.71 (0.61 to 0.79) (0.42 to 0.71) 0.76 (0.63 to 0.87) 0.62 (0.43 to 0.79) 0.73 (0.62 to 0.82) (0.46 to 0.75) 0.69 (0.54 to 0.81) 0.56 (0.39 to 0.72) 0.72 (0.59 to 0.82) Bone marrow iron macrophage iron score (0.48 to 0.77) 0.67 (0.52 to 0.79) 0.55 (0.40 to 0.69) 0.74 (0.60 to 0.85) (0.18 to 0.45) 0.63 (0.48 to 0.76) 0.35 (0.19 to 0.56) 0.58 (0.47 to 0.68) (0.01 to 0.17) 0.71 (0.56 to 0.83) 0.12 (0.02 to 0.39) 0.53 (0.46 to 0.60) bone marrow iron stores (deplete versus replete) 0.63 (0.48 to 0.77) 0.67 (0.52 to 0.79) 0.56 (0.40 to 0.71) 0.73 (0.60 to 0.84) Data are presented as mean (95% Cl). a Pretest probability of response 0.4. Table 3. Relationship between the index test (a 1-g/dl increase in Hb) and the reference tests in a model of multivariable binary logistic regression analysis Variable a B SE Wald df P Exp(B) (95% CI) TSAT (0.88 to 0.98) Ferritin (0.99 to 1.00) Constant Cox and Snell R ( ; dif 2; P 0.001). a Variables entered on step 1: Gender, age, Hb, CRP, TSAT, ferritin, GFR, and bone marrow iron (deplete or replete). found no correlation among TSAT, ferritin, and the erythropoietic response, although 90% of patients were iron deplete, but the number of patients was low. More data are needed to clarify this issue. A 1-g/dl increase in Hb was noted in one third of our patients without deplete bone marrow iron stores. This is similar to data from HD patients in the DRIVE study (30), in which peripheral iron indices were also not reliable predictors of response. Given the reduced prognostic utility of peripheral iron indices and even of the bone marrow stores for a positive response, a therapeutic trial with 1000 mg of intravenous iron seems to be more useful, but its practice should be carefully weighed against the potential deleterious effect of iron (13,14). What are the limits of this study? The assessment of bone marrow iron stores was made by a qualitative method on an aspirate, and a recent study that used a quantitative method proved a strong relationship between iron stores and ferritin in HD patients (33). To overcome these, not only macrophage iron was considered but also the sideroblasts, and a sufficient number of slides were examined (17). Moreover, relationships were found between iron stores and response. The number of participants, also one of the highest reported, still may be too small, and the composition of patients is different from the other reported series by the low proportion of patients with diabetes, the distribution skewed toward advanced CKD stages, more severe anemia, and highly prevalent inflammation. The high prevalence of inflammation (60% with a CRP 10 mg/l) seems not unusual in patients with anemia and advanced CKD, because recent reports gave similar proportions (74%) (34). In other studies, a correlation was found between CRP and ferritin, because ferritin is an acute-phase reactant and its utility in guiding iron therapy was questioned (4,30,35 37). An influence of inflammation on the erythropoi-

7 Clin J Am Soc Nephrol 5: , 2010 Can Response to Iron Be Predicted? 415 etic response is not sustained by our data, because no correlation was found between CRP and iron indices, and, similar to HD patients (3), neither in univariable analysis nor in the logistic regression did the CRP level have any influence on the response. The initial Hb level was linked to the response to intravenous iron (7,9), a relationship that was not found in our study, probably because of the severity of anemia in our patients. Nevertheless, all these characteristics are commonly found in day-to-day practice, and even if they could generate some statistical biases, they should be considered in the clinical decision. Conclusions Half of nondialysis patients with CKD responded with a 1-g/dl increase in Hb one month after 1000 mg of intravenous iron. Because even one third of patients with iron-replete bone marrow stores responded, whereas iron indices had a moderate accuracy in predicting the response, the therapeutic intravenous iron trial seems to be a useful tool in the management of anemia in nondialysis patients with CKD. Acknowledgments Part of this research was supported by a grant from Anemia Working Group, Romania. Part of this work was presented as a poster at World Congress of Nephrology; May 22 through 26, 2009; Milan, Italy. Disclosures None. References 1. KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. 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